Tumor necrosis factor-α (TNF-α), a pleiotropic cytokine, is produced mainly by macrophages, but it may be produced by other types of cells also. TNF-α demonstrates beneficial as well as pathological activities. It has both growth stimulating effects and growth inhibitory properties, besides being self-regulatory. The beneficial functions of TNF-α include maintaining homeostasis by regulating the body's circadian rhythm, mounting an immune response to bacterial, viral, fungal and parasitic infections, replacing or remodeling injured tissue by stimulating fibroblast growth and as the name suggests, killing certain tumors.
Tumor necrosis factor-α (TNF-α) has been implicated as a mediator in inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, ulcerative colitis, psoriasis, adult respiratory distress syndrome, diabetes, delayed-type hypersensitivity in skin disorders and Alzheimer's disease.
Interleukin-1 (IL-1) is an important part of the innate immune system, which regulates functions of the adaptive immune system. The balance between IL-1 and IL-1 receptor antagonist (IL-1ra) in local tissues influences the possible development of inflammatory disease and resultant structural damage. In the presence of an excess amount of IL-1, inflammatory and autoimmune diseases may develop in the joints, lungs, gastrointestinal tract, central nervous system (CNS) or blood vessels.
Inflammation is the response of a tissue to injury that may be caused by a biological assault such as invading organisms and parasites, ischemia, antigen-antibody reactions or other forms of physical or chemical. injury. It is characterized by increased blood flow to the tissue, causing pyrexia, erythema, induration and pain. Cytokines, especially interleukins (IL-1, IL-6, IL-8) and TNF-α play an important role in the inflammatory process. Both IL-1 and TNF-α are derived from mononuclear cells and macrophages and in turn induce the expression of a variety of genes that contribute to the inflammatory process. An increase in TNF-α synthesis/release is a common phenomenon during the inflammatory process. Inflammation is an inherent part of various disease states like rheumatoid arthritis, Crohn's disease, septic shock syndrome and atherosclerosis, among other clinical conditions.
Among various inflammatory disorders, rheumatoid arthritis (RA) is an autoimmune disorder. RA is a chronic, systemic, articular inflammatory disease of unknown etiology. In RA, the normally thin synovial lining of joints is replaced by an inflammatory, highly vascularized, invasive fibrocollagenase tissue (pannus), which is destructive to both cartilage and bone. Areas that may be affected include the joints of the hands, wrists, neck, jaw, elbows, knee, feet and ankles. Cartilage destruction in RA is linked to aberrant cytokines and growth factor expression in the affected joints.
Interleukin 1-β (IL-1β) and TNF-α are the key inflammatory cytokines in rheumatoid arthritis (RA), osteoarthritis (OA) and other autoimmune conditions. RA synovium is characterized by an imbalance between IL-1 receptor antagonist (IL-1ra) and IL-1β production, in favour of the latter. Two clinically important cytokines released in the synovium are IL-1 and TNF-α. The cytokines IL-1β and TNF-α increase the production of cyclo-oxygenase-2 (COX-2), nitric oxide, adhesion molecules, IL-6, chemokines, and collagenases. Both IL-1β and TNF-α stimulate the production of one another. IL-1β contributes to increased osteoclast activation and angiogenesis and TNF-α increases apoptosis. The actions of these and other cytokines lead to the clinical manifestations of the disease.
The first line of treatment for inflammatory disorders involves the use of nonsteroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, naproxen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Morever, NSAIDs merely treat the symptoms of disorder and not the cause. When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
Hence, there is a need for improved and alternative medicaments for the prevention and treatment of inflammatory disorders caused by increased IL-1 and TNF-α.
Herbs have been known and used throughout the world for treatment of many conditions. There is evidence that products derived from plants have potential pharmacological and therapeutic effects on mammals and tend to have less deleterious side effects than synthetic drugs.
The present invention describes a novel herbal composition, which comprises extract of leaves of the plant Polyalthia longifolia. The composition can be used for treatment of various inflammatory disorders with minimal side effects.
Polyalthia longifolia, widely distributed throughout India, is a tall, evergreen, pyramid-like, straight undivided ornamental tree containing simple, green leaves with shining undulate margins. It belongs to the family Annonaceae and is popularly known as Ashoka. The plant is useful in fever, skin diseases, hypertension and vitiated conditions of vata and pifta, as per the traditional Ayurvedic System of Medicine.
Clerodane diterpenoids from Polyalthia longifolia have been reported to have antifeedant properties. (Phytochemistry, 27(9), 2899-2901, (1988)).
Clerodane diterpenes have been isolated from stem bark of Polyalthia longifolia and were evaluated for cytotoxicity. The studies suggest potential antitumor applications for these compounds. (Planta Medica, 57(4), 380-383, (1991)).
Isolation of a compound 16-oxa-cleroda-3,13E-diene-15-oic acid from Polyalthia longifolia has been reported The compound exhibited activity against IκBα kinase. (Indian Journal of Chemistry, 39B (10), 801-802, (2000)).
Antimicrobial activity of clerodane diterpenoids has been reported from Polyalthia longifolia seeds. (Fitoterapia, 76, 336-339, (2005)).
To our knowledge, there is no report of any medicament containing extract of the plant Polyalthia longifolia for treatment of inflammatory disorders.
To overcome the problems of side effects of present line of treatment, such as allergy induction, activation of latent tuberculosis, myelosuppression, increased risk of cancer and congestive heart disease, associated with the prior art compositions, the present inventors have prepared a novel herbal composition having IL-1 and TNF-α inhibitory activity, effective against inflammation, which can be used optionally in combination with other bioactive substances.